Prolonged elevation of plasma non-esterified fatty acids (NEFAs) induces insulin resistance and impairs pancreatic -cell adaptation to insulin resistance. Studies in rodents suggest that inflammation may play a role in this 'lipotoxicity'. We studied the effects of sodium salicylate, an anti-inflammatory agent, on lipid-induced alterations in -cell function and insulin sensitivity in 6 overweight and obese, non-diabetic men. Each subject underwent 4 separate studies, 4-6 weeks apart, in random order: 1) SAL, 1 week placebo followed by i.v. infusion of saline for 48 h; 2) IH, 1 week placebo followed by i.v. infusion of Intralipid plus heparin for 48 h to raise plasma NEFAs ~2 fold; 3) IH+SS, 1 week sodium salicylate (4.5 g/d) followed by 48 h IH infusion; and 4) SS, 1 week oral sodium salicylate followed by 48 h saline infusion. After 48 h saline or lipid infusion, insulin secretion and sensitivity were assessed by hyperglycemic clamp and euglycemic-hyperinsulinemic clamp, respectively, in sequential order. Insulin sensitivity was reduced by lipid infusion (IH = 67% of SAL), and was not improved by salicylate (IH+SS = 56% of SAL). Lipid infusion also reduced the disposition index (p<0.05), which was not prevented by sodium salicylate. Salicylate reduced insulin clearance. These data suggest that oral sodium salicylate at this dose impairs insulin clearance but does not ameliorate lipid-induced insulin resistance and -cell dysfunction in overweight and obese, non-diabetic men.